Over the past decades, the influence of smoking or MetS on CRC has been widely investigated. Smoking has been demonstrated to have a significant association with tumorigenesis and poor CRC prognosis8,13,14,15. By studying 2548 CRC survivors, Baiyu Yang et al.8 indicated that pre- and post-diagnosis smoking status was associated with CRC-specific mortality. However, the association between MetS and CRC is currently unclear. As reported by some studies, MetS is a risk factor for CRC16,17,18,19. Moreover, several studies have demonstrated that CRC patients with MetS may have worse prognoses that CRC patients without MetS. Moreover, Jason R et al.20 found that male subjects with MetS had significantly higher risk of mortality from CRC than did male subjects without MetS. Two other studies also found similar results21,22. By studying 507 CRC patients, Shen Z et al.23 found that MetS was positively related to higher mortality and recurrence. You J et al.11 evaluated 1069 CRC patients and demonstrated that MetS was associated with an increased recurrence risk. However, some studies showed opposite results12. Nevertheless, until now, no study has investigated the additive effect of smoking and MetS on CRC prognoses. Thus, the present study aimed to investigate the potential individual and combined effect of smoking and MetS on the prognosis of CRC.
Initially, we found that MetS was independently associated with RFS and not OS, which is consistent with the findings of another study11. However, the present study employed the Chinese criteria for diagnosing MetS that are slightly different from the criteria in the abovementioned studies. Additionally, the participants were all Southeast Chinese males, who have unique dietary habits and heredity features. Previous studies have indicated that varying definitions of MetS and different races might influence clinical outcomes24,25,26 and thus partially explained the differences between the present study and others. Furthermore, the synergistic effect of MetS was determined using all of its components, which not only have complicated mechanisms but also are far from clear. The present study indicated that elevated BP and hyperglycemia have a negative effect on OS and RFS, while dyslipidemia exerts a positive effects on OS and RFS. Thus, we speculated that the protective effect of dyslipidemia on survival may have counteracted the effect of the two other risk factors and finally led to nonsignificant effects on OS. However, of those three significant components, elevated BP and hyperglycemia had dominant effects on RFS and resulted in poor RFS. The underlying mechanism should be further studied in the future. On the other hand, smoking status was significantly related to OS and RFS. In fact, there was no difference between “never” and “former” smokers regarding OS and RFS in Cox analyses, consistent with the results of another study8. Thus, we combined “former” and “never” smokers into the non-smoker group. Further evaluation on patients categorized into four groups based on their smoking and MetS status showed that smoking and MetS had significant additive effect on RFS.
At present, the potential mechanisms underlying the combined effect of smoking and MetS are not clearly understood. As indicated by previous studies, MetS may cause or promote CRC development and progression via various mechanisms, including dysregulation of growth signals, inflammatory cytokines, and vascular integrity factors27. Inflammation can contribute to the development, progression, and recurrence of tumors, including CRC28,29. More specifically, COX2, which involved in various inflammatory pathways, can promote the recurrence of adenomas and sporadic adenomatous polyps30,31,32. In addition, high expression of COX2 can induce CRC tumorigenesis and metastasis33. On the other hand, smoking can lead to inflammation through multiple mechanisms, including the regulation of secretion of tumor necrosis factor34,35,36. Smoking has been shown to induce inflammation associated with numerous diseases including CRC37,38. We observed an additive effect of smoking and MetS on recurrence. Hence, we hypothesized that inflammation may be a common mechanism underlying the pathophysiological process of recurrence induced by both MetS and smoking. However, the detailed mechanism should be further studied.
Previous studies have demonstrated that metformin may exert anti-cancer effects and reduce the incidence of various cancers, including CRC39. The association between metformin and CRC prognosis remains controversial. Based on our results, metformin appeared to play protective roles regarding both OS and RFS for CRC patients, consistent with the results of other studies40,41. However, some other studies did not support the protective association between metformin treatment and CRC prognosis42.
To the best of our knowledge, this is the first study examining the combined effect of smoking and MetS on CRC prognosis. Studies have indicated that metformin and statin treatment may play anti-cancer roles in various cancers39,43, but these effects have been neglected in numerous other studies. Thus, in the present study, we controlled for the confounding effects of metformin and statin and obtained more reasonable and reliable results. However, several limitations still exist. First, the observational study design does not provide evidence regarding the potential mechanism of the combined effect of smoking and MetS on recurrence. Second, the relatively short duration of follow-up, single center focus, and a small number of current smokers may weaken the results of the present study. Third, although the definition of MetS in the present study has been used in investigating various diseases44,45,46,47, it is not used worldwide. However, due to the unique hereditary and dietary features, this definition is suitable for the Chinese population. Finally, residual confounding cannot be avoided owing to the characteristics of observational studies. Indeed, we could not exclude the possibility of the effect of uncontrolled or inadequately measured confounders on the results. Therefore, a large multicenter prospective study with long-term follow-up should be implemented in the future.
Source : https://www.nature.com/articles/s41598-018-19322-0